Elucidation of autophagy inhibition mechanism by macrolide antibiotics and therapeutic application to multiple myeloma.
| Project/Area Number |
16K19187
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Applied pharmacology
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| Research Institution | Tokyo Medical University |
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Principal Investigator |
Moriya Shota 東京医科大学, 医学部, 助教 (30634935)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | 骨髄腫 / オートファジー / マクロライド / 小胞体ストレス / プロテアソーム / ボルテゾミブ / クラリスロマイシン / 微小環境 / ベルケイド / bortezomib / 多発性骨髄腫 / リソソーム |
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| Outline of Final Research Achievements |
We previously reported that macrolide antibiotics including clarithromycin (CAM) have an inhibitory effect on autophagy flux, and combined treatment with a proteasome inhibitor bortezomib (BZ) leads to enhanced apoptosis induction via endoplasmic reticulum (ER) stress overloading in multiple myeloma (MM) cells. Since bone marrow microenvironment supports the myeloma cell growth and induces cell adhesion-mediated drug resistance (CAM-DR), we investigated the cytotoxic effect of BZ plus macrolide combination using the co-culture system of EGFP-labelled MM cell lines and stroma cell lines. EGFP-MM cells were charged onto the stroma cell monolayer and co-cultured with BZ in the presence or absence of macrolide. We have observed that the pronounced BZ-induced cytotoxicity by macrolide in MM cells co-cultured on the stroma layer. These data suggest that macrolide could be used as an autophagy inhibitor and combined treatment with BZ plus macrolide can be overcome CAM-DR.
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| Academic Significance and Societal Importance of the Research Achievements |
現在、多発性骨髄腫の治療目標は「完治」でなく「延命」であり、一刻も早い新規治療法の開発が求められている。これまでに研究代表者は、マクロライド抗生剤のオートファジー阻害作用を明らかにし、プロテアソーム阻害剤との併用による「細胞内タンパク分解系の同時阻害」が、骨髄腫細胞株に強力な癌細胞死を誘導することを報告してきた。マクロライドは臨床でのデータが十分蓄積されているため安全性も高く、骨髄腫治療への応用が期待できる薬剤の一つであると考えられる。骨髄腫難治性の原因の一つである微小環境での有効性や、微小環境による薬剤抵抗の分子基盤解明を進めることで、in vivo試験や実臨床に向けた基盤形成とする。
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Report
(4 results)
Research Products
(40 results)
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[Journal Article] Amino acid starvation culture condition sensitizes EGFR-expressing cancer cell lines to gefitinib-mediated cytotoxicity by inducing atypical necroptosis.2018
Author(s)
Saito Y, Moriya S, Kazama H, Hirasawa K, Miyahara K, Kokuba H, Hino H, Kikuchi H, Takano N, Hiramoto M, Tsukahara K, Miyazawa K.
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Journal Title
Int J Oncol.
Volume: 52
Pages: 1165-1177
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines.2016
Author(s)
Mukai S, Moriya S, Hiramoto M, Kazama H, Kokuba H, Che XF, Yokoyama T, Sakamoto S, Sugawara A, Sunazuka T, Omura S, Handa H, Itoi T, Miyazawa K.
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Journal Title
Int J Oncol
Volume: 48
Issue: 1
Pages: 45-54
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Specific autoantigens identified by sera obtained from mice that are immunized with testicular germ cells alone.2016
Author(s)
Terayama H, Hirai S, Naito M, Qu N, Katagiri C, Nagahori K, Hayashi S, Sasaki H, Moriya S, Hiramoto M, Miyazawa K, Hatayama N, Li ZL, Sakabe K, Matsushita M, Itoh M.
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Journal Title
Sci Rep.
Volume: 18
Issue: 1
Pages: 35599-35599
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER stress loading in breast cancer cell lines.2016
Author(s)
Miyahara K, Kazama H, Kokuba H, Komatsu S, Hirota A, Takemura J, Hirasawa K,Moriya S, Abe A, Hiramoto M, Ishikawa T, Miyazawa K.
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Journal Title
Int J Oncol.
Volume: 49
Issue: 5
Pages: 1848-1858
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Macrolide antibiotics exhibit cytotoxiceffect under amino acid-depleted culture condition by blocking autophagy flux in head and neck squamous cell carcinoma cell lines.2016
Author(s)
Hirasawa K, Moriya S, Miyahara K, Kazama H, Hirota A, Takemura J, Abe A, Inazu M, Hiramoto M, Tsukahara K, Miyazawa K.
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Journal Title
PLoS One
Volume: 11
Issue: 12
Pages: 1848-1858
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Presentation] Amino acid-starving culture condition enhances gefitinib-induced cytotoxicity via necroptosis-like cell death in EGFR-expressing cancer cells2017
Author(s)
Saito Y, Moriya S, Kazama H, Hirasawa K, Miyahara K, Kokuba H, Hino H, Kikuchi H, Takano N, Hiramoto M, Tsukahara K, Miyazawa K.
Organizer
第179回 東京医科大学医学会総会
Related Report
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[Presentation] Amino acid-starving culture condition enhances gefitinib-induced cytotoxicity via necroptosis-like cell death in EGFR-expressing cancer cells2017
Author(s)
Saito Y, Moriya S, Kazama H, Hirasawa K, Miyahara K, Kokuba H, Hino H, Kikuchi H, Takano N, Hiramoto M, Tsukahara K, Miyazawa K.
Organizer
第180回 東京医科大学医学会総会 医学会奨励賞受賞講演
Related Report
Invited
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